Ketamine Therapy for Depression: A Canadian Patient Guide

For Canadians with treatment-resistant depression, ketamine therapy offers a fundamentally different mechanism than SSRIs and SNRIs. Where conventional antidepressants take four to six weeks to act on serotonin pathways, ketamine acts on the glutamate system and can produce antidepressant effects within hours. The Canadian Network for Mood and Anxiety Treatments (CANMAT) lists IV racemic ketamine as a third-line treatment for adults with treatment-resistant major depressive disorder (Swainson et al., 2021). This guide covers how ketamine works, the conditions it treats, the modalities available in Canada, and how to access care.

Key takeaways

• Ketamine is most established for treatment-resistant depression — failure of two or more antidepressant trials at therapeutic dose for at least six weeks each.
• Antidepressant effects can emerge within 2 to 72 hours of a single IV dose, sustained days to weeks; serial dosing extends durability.
• Spravato (intranasal esketamine) is Health Canada-approved for treatment-resistant MDD as of May 2020; generic IV/IM/sublingual ketamine is prescribed off-label.
• Most Canadian patients pay out-of-pocket. Provincial drug plans do not cover ketamine for psychiatric use; private insurers typically cover Spravato (with prior authorization), not generic ketamine.
• Ketamine works through NMDA receptor antagonism and downstream BDNF/synaptogenesis — a different pathway from SSRIs/SNRIs.

The case for ketamine in depression

Conventional antidepressants — SSRIs, SNRIs, atypicals — work for roughly half of patients on the first trial. The rest cycle through additional medications, augmentation strategies, and psychotherapy modalities. Patients who fail two or more adequate antidepressant trials are clinically defined as having treatment-resistant depression (TRD).

CANMAT 2021 places single-dose IV racemic ketamine as a third-line treatment for adults with TRD, the strongest level of guideline endorsement ketamine has received in Canada. The accompanying recommendation states that "clinicians administering ketamine should have medical training and qualifications to manage behavioral and cardiovascular adverse events" (Swainson et al., 2021). The Edmonton public ketamine program at Misericordia and Grey Nuns Hospitals — operating since 2015 — reports that early patients in the program had failed an average of 8.1 prior antidepressant trials and 90% had failed electroconvulsive therapy (Chrenek et al., 2024). This is the clinical population for whom ketamine is most established.

How ketamine works for depression

Ketamine acts on the brain's glutamate system, not the serotonin system targeted by SSRIs. The primary mechanism is antagonism at NMDA (N-methyl-D-aspartate) receptors on inhibitory interneurons. Blocking these receptors triggers a downstream surge of glutamate, which activates AMPA receptors and stimulates the release of brain-derived neurotrophic factor (BDNF) along with mTOR signalling. The cumulative effect is rapid synaptogenesis — the formation of new neural connections — within 24 to 72 hours of a single dose.

A 2022 systematic review of 141 studies concluded that "ketamine induces an increase in molecules involved in modulating neuroplasticity" paired with rapid mood improvements (Kang et al., 2022). Aleksandrova and Phillips (2021) frame the mechanism as a "reset" — ketamine counteracts synaptic deficits and restores connectivity between the prefrontal cortex and limbic structures that becomes disrupted in depression (Aleksandrova & Phillips, 2021).

The contrast with conventional antidepressants is the timeline. SSRIs and SNRIs gradually adjust monoamine signalling; clinical benefit emerges over four to six weeks. Ketamine acts on glutamate directly — antidepressant effects can emerge within 2 to 72 hours of a single IV dose (Lullau et al., 2023).

What the evidence shows

The depression evidence base is now substantial. Key studies:

• Berman et al., 2000 — first placebo-controlled RCT in depressed patients; subjects "evidenced significant improvement in depressive symptoms within 72 hours after ketamine but not placebo infusion" (Berman et al., 2000).
• Zarate et al., 2006 — RCT in 18 TRD patients with average 6 prior failed antidepressant trials; "robust and rapid antidepressant effects resulted from a single intravenous dose; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week" (Zarate et al., 2006). This study established the 0.5 mg/kg over 40-minute IV protocol that became the field standard.
• Murrough et al., 2013 — largest active-placebo-controlled RCT (midazolam comparator) at the time; 64% response rate for ketamine versus 28% for midazolam at 24 hours (Murrough et al., 2013).
• Singh et al., 2016 — Phase 2 dose-frequency RCT (n=99); twice-weekly 0.5 mg/kg IV over 3 weeks produced 51% response and 26% remission rates versus 9% and 3% on placebo (Singh et al., 2016).
• Phillips et al., 2019 — Canadian RCT showing repeated ketamine infusions have "cumulative and sustained antidepressant effects"; 59% met response criteria with a median of three infusions (Phillips et al., 2019).
• Marcantoni et al., 2020 — meta-analysis of 28 studies confirming "a strong ketamine effect was observed within 4 hours following a single infusion, and peaked at 24 hours…multiple infusions resulted in an enhanced and prolonged ketamine effect" (Marcantoni et al., 2020).
• Wilkinson et al., 2018 — meta-analysis of 167 patients with baseline suicidal ideation; ketamine produced rapid reductions in suicidal ideation within 24 hours, partially independent of antidepressant response (Wilkinson et al., 2018).

For Spravato (esketamine) specifically:

• Daly et al., 2018 — Phase 2 dose-finding RCT in TRD; intranasal esketamine 28–84 mg twice weekly produced significant dose-dependent improvement at 1 week (Daly et al., 2018).
• Daly et al., 2019 (SUSTAIN-1) — Phase 3 maintenance RCT; continued esketamine plus oral antidepressant decreased relapse risk by 51% in remitters and 70% in responders (Daly et al., 2019).

Aggregate response rates across studies typically fall in the 50–70% range for treatment-resistant samples after a single infusion, with remission rates of 25–40% (Marcantoni et al., 2020). These figures describe group-level outcomes in clinical trials and do not predict individual results.

Ketamine versus traditional antidepressants

The two are not interchangeable. They work on different brain systems, on different timelines, and serve different positions in the care pathway.

CANMAT 2021 explicitly positions ketamine after multiple antidepressant trials have failed. Most Canadian patients in ketamine programs continue their existing antidepressants alongside ketamine treatment.

What types of ketamine therapy are available?

Five delivery routes are used clinically. Each has a different bioavailability, evidence base, regulatory status, and typical session experience.

IV infusion remains the gold standard for evidence: most psychiatric RCTs used IV ketamine. KAP-style protocols using IM and sublingual are widely used in Canadian clinics, often with integrated psychotherapy. Spravato is the only ketamine-class drug Health Canada has approved for a psychiatric indication, and it is the form most likely to attract private insurance coverage.

Spravato versus generic ketamine — what's the difference?

The two are different molecules administered through different routes.

Spravato (esketamine) is the S-enantiomer of ketamine, delivered as a nasal spray. Health Canada issued a Notice of Compliance in May 2020 for use, in combination with an oral SSRI or SNRI, in adults with treatment-resistant MDD (Health Canada DPD). Spravato must be administered in a certified clinical setting under direct healthcare supervision; the Janssen Journey program controls distribution. CADTH's Common Drug Review recommended against public reimbursement in December 2020, so most provincial drug plans do not list it. Some private insurers and federal programs (Veterans Affairs Canada, WSIB Ontario, WCB Alberta) cover Spravato with prior authorization.

Generic racemic ketamine is a 50/50 mixture of R-ketamine and S-ketamine. It is approved in Canada only as an anaesthetic. Use for depression is off-label — a legal and common practice in Canadian medicine. It is delivered IV, IM, sublingually, or orally, typically priced out-of-pocket, and has the largest psychiatric evidence base because most RCTs used IV ketamine.

The choice is driven by indication, prior treatment history, insurance coverage, and what's available locally. For Canadians with treatment-resistant MDD and access to a Spravato-prescribing clinic, esketamine has the clearest regulatory and coverage pathway. For patients seeking the deepest evidence base or who want ketamine-assisted psychotherapy with integrated therapist support, IV or IM ketamine remains the most-studied form.

Ketamine-assisted psychotherapy: why pairing matters

When ketamine is paired with structured psychotherapy before, during, and after dosing, the treatment is called ketamine-assisted psychotherapy (KAP). Ketamine alone is the medical model — drug administered, follow-up medical visits, no integrated therapy.

A 2022 systematic review of 17 KAP studies (n=603) concluded: "Psychotherapy, provided before, during, and following ketamine sessions, can maximize and prolong benefits" (Drozdz et al., 2022). A 2017 trial demonstrated that adding 12 weeks of cognitive-behavioural therapy after a 4-session IV ketamine course extended antidepressant durability — relapse occurred in only 25% of responders by week 8, compared with 55–89% in comparable open-label ketamine-only protocols (Wilkinson et al., 2017).

The neurobiology supports the pairing. Ketamine opens a window of heightened neuroplasticity lasting roughly 24 to 72 hours post-dose. Psychotherapy conducted within and after that window helps consolidate new cognitive and emotional patterns into the newly formed synaptic architecture.

ATMA CENA's ketamine programs use the KAP model. Two dosing modes are offered: psychedelic (higher dose, altered-state experience) and psycholytic (lower dose with the patient engaged in talk therapy).

Who is a candidate for ketamine therapy for depression?

Most Canadian ketamine clinics use the following inclusion criteria:

• Adults 18 or older
• Diagnosis of treatment-resistant major depressive disorder (failure of at least two adequate antidepressant trials at therapeutic dose for at least six weeks each, plus at least one adjunctive medication trial)
• For Spravato specifically: documented TRD per the Health Canada label
• Medically stable; able to provide informed consent
• Willing to engage in preparation and integration sessions where the program includes them

Absolute contraindications include active psychosis or schizophrenia spectrum disorder, uncontrolled severe hypertension, severe cardiovascular disease, increased intracranial pressure, current pregnancy, anaphylactic reaction to ketamine, and active manic episode. Relative contraindications — requiring careful evaluation but not automatically excluding — include history of substance use disorder, severe personality disorder with marked instability, recent stroke, untreated severe sleep apnea, and concurrent use of MAOIs or high-dose benzodiazepines (which may attenuate the antidepressant effect; see Andrashko et al., 2021).

For a full breakdown of eligibility and the screening process, see How to Qualify for Ketamine Therapy in Canada.

How many sessions are needed?

Most acute protocols involve 4 to 8 sessions over 2 to 4 weeks. Spravato has a defined induction phase: twice weekly for 4 weeks, then weekly for 4 weeks, with maintenance dosing weekly or every 2 weeks thereafter (Daly et al., 2018). IV ketamine protocols vary — 6 infusions over 2 to 3 weeks is the most common acute pattern. Phillips et al. (2019) reported a median of 3 infusions to reach response with weekly maintenance sustaining gains (Phillips et al., 2019).

After the acute phase, many patients return for periodic maintenance sessions. The right number depends on individual response and clinical judgement.

What does ketamine therapy cost in Canada?

Most Canadian patients pay out-of-pocket. Provincial public health plans do not cover ketamine for psychiatric indications. Typical ranges:

• IV ketamine: CAD $375–$1,000 per session; 6-session course CAD $2,250–$5,400
• Ketamine-assisted psychotherapy (with therapist): CAD $685–$1,400 per session
• Spravato (esketamine): CAD $250–$800 per session including drug + administration; 4-week induction CAD $5,000–$7,000 without coverage

ATMA CENA publishes pricing for its KAT programs at ATMA CENA's published pricing page: KAT Psychedelic Pathway from CAD $1,585 + $795 per additional session; KAT Psycholytic Pathway from CAD $1,530 + $740 per additional session; customized programs CAD $2,325–$6,930. Coverage exceptions include Alberta Blue Cross (effective March 2024), WCB Alberta, WSIB Ontario, and Veterans Affairs Canada. For the full pricing breakdown, see Ketamine Therapy Cost in Canada.

Safety and side effects

At sub-anaesthetic doses with proper screening and supervised administration, ketamine has a well-established short-term safety profile. Common side effects:

• Dissociation or perceptual changes during the dosing window (resolves within 1–3 hours)
• Mild nausea
• Transient elevation in blood pressure (typically 10–30 mmHg) and heart rate
• Dizziness or unsteadiness
• Headache

Sessions are conducted with continuous vital-sign monitoring. Patients cannot drive for at least 24 hours after a session. Dependency risk is low at therapeutic doses in supervised contexts; active ketamine use disorder is a contraindication.

Long-term safety considerations from heavier or unsupervised use — bladder toxicity, hepatic and biliary effects, dependency — are linked to high-frequency, high-dose, unsupervised exposure rather than the controlled clinical dosing used in therapy. Health Canada has issued a safety review noting hepatotoxicity and cholangiopathy risk with extended ketamine exposure; baseline and ongoing liver-function monitoring is appropriate for patients receiving maintenance infusions.

How to access ketamine therapy for depression in Canada

The path from "I want to try this" to first session typically follows six steps:

1. Initial inquiry. Most private Canadian ketamine clinics, including ATMA CENA, accept self-referrals. Public programs (Vancouver Coastal Health UBC Hospital; Edmonton Misericordia and Grey Nuns) require psychiatrist referral.
2. Intake questionnaire. Health history covering psychiatric history, medications, physical health, prior treatments.
3. Clinical consultation. A 45–60 minute video or in-person consultation with a physician, psychiatrist, or NP. Diagnostic confirmation, treatment-failure documentation, contraindication screening, suicide risk assessment.
4. Medical clearance. Cardiovascular workup including baseline blood pressure (both arms), heart rate, and ECG. CANMAT 2021 mandates ECG before infusion.
5. Informed consent and treatment plan. Sessions, modality, and integration approach. Consent documented in writing.
6. First session scheduled. Most private Canadian clinics move from initial inquiry to first session within 2 to 4 weeks once cleared.

Frequently asked questions

How is ketamine different from traditional antidepressants? Ketamine acts on the glutamate system; SSRIs and SNRIs act on serotonin and norepinephrine. Ketamine produces effects within 2 to 72 hours; conventional antidepressants take 4 to 6 weeks. Ketamine is delivered as a course of clinical sessions; SSRIs and SNRIs are taken daily.

How quickly does ketamine work for depression? Antidepressant effects can emerge within 2 to 72 hours of a single IV dose. Peak effect for a single session is typically 24 to 48 hours post-infusion. Durability of a single session is days to weeks; serial dosing extends durability.

How many ketamine treatments are needed for depression? Most acute IV protocols involve 6 sessions over 2 to 3 weeks. Spravato has a defined 4-week induction (twice weekly for 4 weeks) followed by 4 weeks of weekly dosing. Many patients return for periodic maintenance sessions. The right number depends on individual response.

What is treatment-resistant depression? The CANMAT 2021 definition: failure of at least two adequate antidepressant trials from different pharmacological classes plus at least one adjunctive medication trial. "Adequate" means therapeutic dose for at least 6 weeks per trial.

Is ketamine therapy covered by insurance in Canada? Provincial health plans do not cover ketamine for psychiatric use. Private insurers typically cover Spravato with prior authorization for TRD; they generally do not cover off-label IV/IM ketamine. Alberta Blue Cross covers psychedelic-assisted therapy including ketamine for eligible plans (effective March 2024). WCB Alberta and WSIB Ontario cover compensable injury cases.

Can I stay on my current antidepressants while doing ketamine therapy? Most Canadian clinics keep patients on their existing antidepressants during ketamine treatment. Some medications interact pharmacodynamically with ketamine — particularly high-dose benzodiazepines (which may attenuate the antidepressant effect) and MAOIs. Discuss any medication adjustments with the prescribing physician at intake.

Is ketamine therapy safe for someone with suicidal ideation? Wilkinson et al. (2018) showed that single-dose ketamine produced rapid reductions in suicidal ideation within 24 hours, with the effect partly independent of antidepressant response. Active suicidal crisis requiring inpatient monitoring is a reason to defer outpatient ketamine until stabilized; individualized clinical assessment is essential.

Can I do ketamine therapy while breastfeeding or pregnant? Pregnancy is an absolute contraindication. Breastfeeding is a relative contraindication; ketamine is excreted in breast milk and risks to the infant are not fully characterized. Discuss with your prescriber.

What's the difference between ketamine therapy and recreational ketamine use? Therapeutic ketamine is administered in a clinical setting at sub-anaesthetic doses by trained medical staff, with screening for medical and psychiatric contraindications and structured psychotherapy support. Recreational use occurs without medical screening, dose control, monitoring, or integration. The bladder toxicity, hepatic effects, and dependency risk associated with recreational ketamine are linked to high-frequency, high-dose, unsupervised exposure — not controlled clinical dosing.

How does ketamine compare to ECT for severe depression? Both are options for treatment-resistant depression. ECT has the longer evidence base and is more widely covered by provincial plans but requires general anaesthesia and may produce cognitive side effects. Ketamine produces effects faster, requires no general anaesthesia, and is typically tolerated with milder cognitive effects. The Edmonton public ketamine program reports that 90% of its early ultra-resistant patients had failed ECT before referral (Chrenek et al., 2024).

Sources

1. ATMA CENA — Ketamine Therapy Hub: https://psychedelic.healthcare/ketamine-therapy/
2. ATMA CENA — Psychedelic-Assisted Therapy: https://psychedelic.healthcare/
3. Health Canada — Drug Product Database (Spravato): https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=98903
4. CADTH / CDA-AMC — Esketamine Reimbursement Review: https://www.cda-amc.ca/esketamine-hydrochloride
5. Berman RM, et al. (2000). Antidepressant effects of ketamine. Biol Psychiatry. https://pubmed.ncbi.nlm.nih.gov/10686270/
6. Zarate CA Jr, et al. (2006). Ketamine in TRD. Arch Gen Psychiatry. https://pubmed.ncbi.nlm.nih.gov/16894061/
7. Murrough JW, et al. (2013). Ketamine TRD active-placebo RCT. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/23982301/
8. Singh JB, et al. (2016). Ketamine dose-frequency RCT. Am J Psychiatry. https://psychiatryonline.org/doi/10.1176/appi.ajp.2016.16010037
9. Phillips JL, et al. (2019). Repeated and maintenance ketamine RCT. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/30922101/
10. Murrough JW, et al. (2015). Ketamine safety in TRD. J Clin Psychiatry. https://www.psychiatrist.com/jcp/ketamine-safety-tolerability-clinical-trials-treatment/
11. Wilkinson ST, et al. (2017). CBT after ketamine. Psychother Psychosom. https://pmc.ncbi.nlm.nih.gov/articles/PMC5516265/
12. Wilkinson ST, et al. (2018). Maintenance ketamine review. J Clin Psychiatry. https://pubmed.ncbi.nlm.nih.gov/29474009/
13. Wilkinson ST, et al. (2018). Ketamine on suicidal ideation meta-analysis. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/29064903/
14. Witt K, et al. (2020). Ketamine for suicidal ideation meta-analysis. Aust N Z J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/31729893/
15. Marcantoni WS, et al. (2020). IV ketamine TRD meta-analysis. J Affect Disord. https://pubmed.ncbi.nlm.nih.gov/33065824/
16. Daly EJ, et al. (2018). Esketamine dose-finding. JAMA Psychiatry. https://pubmed.ncbi.nlm.nih.gov/29282469/
17. Daly EJ, et al. (2019). SUSTAIN-1 esketamine maintenance. JAMA Psychiatry. https://pmc.ncbi.nlm.nih.gov/articles/PMC6551577/
18. Popova V, et al. (2019). TRANSFORM-2 esketamine RCT. Am J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/31109201/
19. Wajs E, et al. (2020). SUSTAIN-2 esketamine long-term safety. J Clin Psychiatry. https://pubmed.ncbi.nlm.nih.gov/32316080/
20. Diazgranados N, et al. (2010). Ketamine in bipolar depression. Arch Gen Psychiatry. https://pubmed.ncbi.nlm.nih.gov/20679587/
21. Zarate CA Jr, et al. (2012). Replication ketamine in bipolar depression. Biol Psychiatry. https://pmc.ncbi.nlm.nih.gov/articles/PMC3343177/
22. Kang MJY, et al. (2022). Ketamine antidepressant mechanisms systematic review. Front Psychiatry. https://pmc.ncbi.nlm.nih.gov/articles/PMC9082546/
23. Aleksandrova LR, Phillips AG (2021). Neuroplasticity ketamine and psychedelics. Trends Pharmacol Sci. https://www.cell.com/trends/pharmacological-sciences/abstract/S0165-6147(21)00157-7
24. Lullau APM, et al. (2023). Antidepressant mechanisms of ketamine. Front Neurosci. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1223145/full
25. Drozdz SJ, et al. (2022). KAP systematic review. J Pain Res. https://pubmed.ncbi.nlm.nih.gov/35734507/
26. Dore J, et al. (2019). KAP outcomes (n=235). J Psychoactive Drugs. https://pubmed.ncbi.nlm.nih.gov/30917760/
27. Swainson J, et al. (2021). CANMAT racemic ketamine recommendations. Can J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/33174760/
28. Chrenek C, et al. (2024). Edmonton community ketamine program. Front Psychiatry. https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2023.1283733/full
29. Andrashko V, et al. (2021). Ketamine drug interactions systematic review. Int J Neuropsychopharmacol. https://pmc.ncbi.nlm.nih.gov/articles/PMC8538895/

Related articles

• Ketamine Therapy in Canada
• What Is Ketamine Therapy?
• Ketamine Therapy Cost in Canada
• How to Qualify for Ketamine Therapy in Canada
• Ketamine Therapy in Calgary
• Ketamine Therapy in Edmonton
• Ketamine vs Psilocybin Therapy
• Alberta Blue Cross Coverage for Psychedelic Therapy
• Workers' Compensation Coverage for Psychedelic Therapy in Alberta

Last updated: 2026-05-05